The present invention is directed to compounds according to the chemical structure I:
Where X or W is each independently N or C—R1;Each Z is independently S, O, N—RN or CR(R);Each R is independently H, a C1-C3 alkyl group optionally substituted with one or two hydroxyl groups or up to three halogen groups or a O—(C1-C3) alkoxy group;Each RN is independently H or a C1-C3 alkyl group optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably H or methyl;Q is O, S, N(R1) or C(RQ)RQ;X1 is O, S, N(R3) or C(RX)RX;RA is H or an optionally substituted C1-C8 alkyl or alkene group, preferably H or a C1-C3 alkyl, most often methyl;RQ and RX are each independently H or a C1-C6 (preferably C1-C3) alkyl group which is optionally substituted with one or two hydroxyl groups or up to three halogen groups;R1 and R2 are each independently H or a C1-C3 alkyl group which is optionally substituted with one or two hydroxyl groups or up to three halogen groups;Each R3 when present, is independently H, a C1-C6 alkyl group optionally substituted with 1 or 2 hydroxyl groups or up to three halogen groups (preferably a C1-C3 alkyl group, more preferably methyl), a protecting group PG or a targeting element TE which is linked to X1 (preferably a nitrogen) through a linker LC which is optionally cleavable;n is 0, 1, 2, 3, or 4, preferably 1, 2 or 3 (more preferably 1);RB1 and RB2 are each independently H, a C1-C3 alkyl group which is optionally substituted with one or two hydroxyl groups or up to three halo groups (F, Cl, Br or I, preferably Cl or F, most often F) or together RB1 and RB2 form a cyclopropyl or cyclobutyl group (preferably, RB1 and RB2 are each independently H, methyl or together form a cyclopropyl group);Each RC is independently H, a C1-C12 optionally substituted alkyl or alkene group (preferably substituted with one or two hydroxyl groups, up to five halo groups), a C1-C12 (preferably C2-C12) optionally substituted acyl or ester group, or a —(CH2)n1NR1R2 or a —(CH2)n1SRSRS1 group where RS is absent or a C1-C6 optionally substituted alkyl group (preferably RS is absent or a methyl group—which forms a positive charge on the sulfur group) and R1, R2 and RS1 are each independently H or a C1-C6 optionally substituted alkyl group (preferably a methyl group), a protecting group PG or a targeting element TE which is linked to the nitrogen or sulfur through a linker LC which is optionally cleavable, and n1 is 1-8 (preferably 1, 2, 3, 4 or 5), or RC (preferably no more than one RC) forms a dimer compound through a linker group, the dimer compound according to the general chemical structure(s):
Where each of X, W, Z, R2, R3, RA, n, RB1 and RB2, X1 and RC are the same as for compound I above, andL is a linker group which covalently links the dimeric portions of the molecule to each other, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.
In each of the above compounds, X is preferably N; Z is preferably S, O, N—H or N—CH3 (more preferably S); W is preferably C—H, R is preferably H, methyl or OMe; RA is preferably H or a C1-C3 alkyl, preferably H or methyl; R1 and R2 are each independently preferably H or methyl; R3 is H, methyl, an ester group (oxycarbonyl ester or carboxyester each having a C1-C6 alkyl group, in certain instances a tert-butyl group) a protecting group PG (preferably a BOC group when X1 is N) or a targeting element TE which is linked to X1 through an optionally cleavable linker LC, RB1 and RB2 are each independently H, methyl or together form a cyclopropyl group and RC is H, methyl, a C1-C12 (preferably C2-C12) optionally substituted acyl or ester group, a —(CH2)n1—N(CH3)2 group or a —(CH2)n1SRSRS1 group where RS is absent or a C1-C6 optionally substituted alkyl group (preferably RS is absent or a methyl group—which forms a positive charge on the sulfur group) and R1, R2 and RS1 are each independently H or a C1-C6 optionally substituted alkyl group (preferably a methyl group) and n is 1, 2, 3 or 4 (more preferably 2 or 3) or no more than one RC forms a dimer compound through linker L where L is preferably a —(CH2)mN(R)(CH2)m— group where R is H or a C1-C3 alkyl group (preferably H or methyl) and each m is independently from 1-12 (preferably, 1-10, more preferably 1, 2, 3, 4, 5, or 6).
In another embodiment, the invention is directed to compounds according to the chemical structure:
Where RA is H or an optionally substituted C1-C8 alkyl or alkene group, preferably H or a C1-C3 alkyl, most often methyl;R2 is H or a C1-C3 alkyl group which is optionally substituted with one or two hydroxyl groups or up to three halogen groups;Each R3 is independently H, a C1-C6 alkyl group optionally substituted with 1 or 2 hydroxyl groups or up to three halogen groups (preferably a C1-C3 alkyl group), a protecting group PG or a targeting element TE which is linked to the adjacent nitrogen through a linker Lc which is optionally cleavable;RB1 and RB2 are each independently H, a C1-C3 alkyl group which is optionally substituted with one or two hydroxyl groups or up to three halo groups (F, Cl, Br or I, preferably Cl or F, most often F) or together RB1 and RB2 form a cyclopropyl or cyclobutyl group (preferably, RB1 and RB2 are each independently H, methyl or together form a cyclopropyl group);Each RC is independently H, a C1-C12 optionally substituted alkyl or alkene group (preferably substituted with one or two hydroxyl groups, up to five halo groups), a C1-C12 (preferably C2-C12) optionally substituted acyl or ester group, or a —(CH2)n1NR1R2 or a —(CH2)n1SRSRS1 group where RS is absent or a C1-C6 optionally substituted alkyl group (preferably RS is absent or a methyl group—which forms a positive charge on the sulfur group) and R1, R2 and RS1 are each independently H or a C1-C6 optionally substituted alkyl group (preferably a methyl group), a protecting group PG or a targeting element TE which is linked to the nitrogen through an optionally cleavable linker LC, and n1 is 1-8 (preferably 1, 2, 3, 4 or 5), or RC (preferably no more than one RC) forms a dimer compound through a linker group, the dimer compound according to the general chemical structure(s):
Where RA, R2, R3, RB1, RB2, and RC are the same as above. In these compositions RA is preferably H or a C1-C3 alkyl, preferably H or methyl; R2 is preferably H or methyl; R3 is H, methyl, a protecting group PG (preferably a BOC group) or a targeting element TE which is linked to the adjacent nitrogen through an optionally cleavable linker LC, RB1 and RB2 are each independently H, methyl or together form a cyclopropyl group and RC is H, methyl, a C1-C12 (preferably C2-C12) optionally substituted acyl or ester group, a —(CH2)n1—N(CH3)2 group or a —(CH2)n1SRSRS1 group where RS is absent or a C1-C6 optionally substituted alkyl group (preferably RS is absent or a methyl group—which forms a positive charge on the sulfur group) and R1, R2 and RS1 are each independently H or a C1-C6 optionally substituted alkyl group (preferably a methyl group) and n1 is 1, 2, 3 or 4 (more preferably 2 or 3) or one RC (no more than one RC) forms a dimer compound through linker L where L is preferably a —(CH2)mN(R)(CH2)m— group where R is H or a C1-C3 alkyl group (preferably H or methyl) and each m is independently from 1-12 (preferably, 1-10, more preferably 1, 2, 3, 4, 5, or 6), oror a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.
In another embodiment, preferred compounds according to the present invention include compounds according to the chemical structure:
or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.
In an alternative embodiment, the present invention is directed to pharmaceutical compositions comprising an effective amount of at least one compound as described above, optionally in combination with at least one additional bioactive agent, preferably at least one additional anticancer agent.
In a further aspect of the invention, compounds according to the present invention are used to treat and/or reduce the likelihood of cancer in a patient in need thereof and to treat or reduce the likelihood that a cancer will metastasize or that a cancer in remission will reoccur (recurrence). The method of treating cancer comprises administering to a patient in need an effective amount of a compound as otherwise described herein in combination with a pharmaceutically acceptable carrier, additive or excipient, optionally in further combination with at least one additional bioactive agent, preferably an agent which is effective in treating cancer, metastatic cancer, recurrent cancer or one or more of its secondary conditions or effects.
Additional embodiments of the present invention are readily gleaned from a review of the Detailed Description of the Invention which Follows.